Heterocyclic nitrogen compounds



United States Patent 3,247,213 v HETEROCYCLIC NITROGEN COMPOUNDS Karl H.Biichel, Beuel (Rhine), Hans J. Schulze-Steinen,

Gut Drechen uber Werl, and Friedrich W. A. G. K.

Korte, Hangelar uber Siegburg, Germany, assignors to Shell Oil Company,New York, N.Y., a corporation of Delaware t I No Drawing. A Filed Jan,29, 19 62, Ser. No. 169,604

Claims priority, applicSati7o3n Germany, Apr. 12, 1961,

6 Claims. 61. 260-291) This invention relates to novel heterocyclicnitrogen compounds and to a general process for the production of'heterocyclic nitrogen compounds.

It is known [Angewandte Chemie, 71, 719 (1959)] that in acid catalyzedhydrolysis alpha-acyl-gammalactones and alp'ha-acyl-delta-lactones canbe readily converted in a single step into the corresponding4,5-dihydrofuran-3-carboxylic acid and 5,6-dihydropyran-3- carboxylicacid, respectively. The conversion proceeds according to the generalreaction which is exemplified for an alpha-acyl-delta-lactone in thefollowing equation:

wherein the symbols (:1) and (b) identify the same carbon atoms in theequations.

Hitherto it has not been possibleto carry out the above conversion withan alpha-acyl lactam in place of an alpha-acyl lactone. [See, forexample, G: Romer, Thesis, University of Bonn, page 76 (1959) and H.Mader, Thesis, University of Bonn, pages 34-37 (1960).] It is known [Ben61, page 327 (1928)] that a hydrolytic ring-opening of alpha-acyllactams with deca rboxylation can be achieved by heating them to 130 C.with concentrated hydrochloric acid in a bomb. It is then necessary toclose the ring and this recyclization to the hetero ring is onlypossible by indirect means, for example, in the synthesis of nicotineaccording to the following scheme:

ice

The syntheses of myosmine (Ber. 69 (1936) page 757) and ana'basine (Ber.69 (1936) page 1082) are similar but with the omission of the iodizationstep It will be understood that the said known syntheses are usuallycarried out in a bomb at high temperatures in more than one step, and inthree or four steps as shown in the above examples.

It has now been found that alpha-acyl-N-alkyl-gammaand delta-lactams, aswell as 'alpha-acyl-N-acyl-gammaand delta-lactams, can be convertedrespectively into unsaturated N-heterocyclic amines orcarboxylic acidsby merely heating them in aqueous acids.

It is an object of the present invention to provide a class of novelnitrogen containingcompounds with unusually good properties asinsecticides, It is a further object of the present invention to providea convenient process for the preparation of these and other usefulcompounds. Further objects of the invention are set forth in thefollowing detailed disclosure of the invention.

The invention therefore relates to a process for the production ofheterocyclic nitrogen compounds having the following formulas:

posite reactions may thus be represented by the following equations:

In the above formulas and equations, R is selected from the groupconsisting of the hydrogen atom, alkyl, aryl, alkaryl, carboxyl,carbalkoxy (alkoxycarbonyl), radicals of from 1 to 20 carbon atoms, andheterocyclic radicals of from 4 to 6 ring atoms in which the hetero atomis a member of the group consisting of nitrogen and the c'halkogens.When the hetro atom is a chalkogen, elements of atomic number from 8 to16, inclusive, are preferred and S). Thus, a class of particularlysuitable hetero atoins are those elements of atomic number N whereinwhere n is a whole number from 0 to 1, m is a whole number from 1 to 2,and n-l-m is 1 to 2. Y represents a methylene bridge of from 2 to 3methylene groups. These methylene groups may be substituted by membersselected from the group consisting of alkyl, aryl, alkaryl, carboxyl andcarbalkoxy radicals. Specific examples of appropriate alkyl groupsinclude methyl, ethyl, propyl, butyl, and in general alkyl groups offrom 1 to 10 carbon atoms are suitable. Alkyl groups of from 1 to 6carbon atoms are preferred. Suitable aryl groups include the phenylgroup and alkyl-substituted phenyl groups (including phenyl groups withfrom 1 to alkyl substituents). Lower alkyl substituents (l to 4 carbonatoms) are most suitable. Condensed ring systems such as the naphthylradical are also suitable as well as the monovalent radical formed frombiphenyl by removal of a hydrogen atom. Suitable carbalkoxy(alkoxycarbonyl) groups are the carbmethoxy (COOCH carbethoxy (--COOC Hcarbpropoxy (-COOC3H7), and carbutoxy radicals. Carbalkoxy(alkoxycarbonyl) radicals with from 1 to 12 carbon atoms in the alkoxymoiety may be used. The symbol Z represents an alkyl or acyl group. WhenZ is alkyl, Z may be any of the alkyl groups described in the definitionof R or in the definition of the substituents on the methylene group, Y.When Z is an acyl group, Z may be represented by the group:

wherein R has the previously defined meaning. When R is a heterocyclicsystem, R may be pyridyl, thiophenyl, furanyl, as well as homologs ofthese radicals formed from alkyl-substituted pyridine, thiophene andfuran. Homologs of thiophene can be made by the reaction of1,4-diketones with phosphorus pentasulfide according to the reaction:

TIC-CH wherein R and R are each alkyl radicals of from 1 to 6 carbonatoms. Similar reactions of 1,4-diketones lead to substituted furans andpyrroles. Radicals formed from substituted dihydropyridines are alsosuitable.

Many of the compounds of the present invention are resonance stabilized.That is,'electron shifts within the molecule which do not disturb thespatial relationships of the atoms are possible. Such shifts allow thedouble bonds in structures such as thiophene and pyrrole to appearbetween different atoms. Thus, the equations:

H II H represent the various structures which may result from electronicshifts. In this application it is to be understood that the conventionalformulas employed represent resonance hybrids and that structuralformulas formed by shifting electrons are included within the scope ofthe conventional structural formulas. Similar remarks apply to thedescription of the stereoisomers which are included by the planarstructural formulas used in this application.

With an alpha-acyl-N-alkyl-gamrna-lactam, the reaction of the presentinvention proceeds as follows:

II 't t l a E N N R N R a lkyl a lkyl a lkyl In these equations, the a,5 and 7 positions are given in relation to the ring carbonyl as shown inthe equations. Suitable alkyl radicals include methyl, ethyl, propyl,i-propyl, t-butyl, n-butyl, s-but-yl, amyl, and in general alkylradicals with from 1-12 carbon atoms. R may be hydrogen, alkyl,carboxyl, carbalkoxy, aryl, alkaryl, or a heterocyclic nitrogen orchalkogen-containing ring radical with 4 to 6 ring atoms and 1 to 3nitrogen or chalkogen atoms. R may be hydrogen, alkyl, aryl, aralkyl,alkaryl, carboxyl or carbalkoxy (alkoxycarbonyl). Lower alkyl radicals(l-4 carbon atoms) are preferred R substituents. Aryl radicals such asphenyl, the radical formed from biphenyl by removal of a hydrogen atomand naphthyl are suitable. Aralkyl radicals such as benzyl may also beused as well as alkaryl radicals such as tolyl and xylyl. In addition Rmay form an added ring system such as the ring systems characteristic ofthe compounds indole and quinoline.

With an alpha-acyl-N-alkyl-delta-lactam, the reaction proceedssimilarly, where R, R and alkyl have the aforementioned meanings:

I R alkyl alkyl alkyl When an alpha-acyl-N-acyl-gamma-lactam isemployed, the reaction is:

In the case of an alpha-acyl-N-acyl-delta-lactam, the following similarreaction scheme is applicable:

In these equations R and R have the same significance as in the previousequations and X represents an alkyl group of from 1 to 10carbon-tatomsorian aryl group of no more than 20 carbon atoms. Suitablealkyl groups include methyl, ethyl, propyl, butyl, amyl and hexylgroups; alkyl groups of from 1 to 8 carbon atoms are preferred. Arylgroups such as phenyl, tolyl, xylyl, cymyl, cumyl, naphthyl, benzyl,du-ryl and biphenylyl are also suitable X radicals.

Suitable catalysts and reaction media for the acid-catalyzed hydrolysisaccording to the present invention are the mineral acids (for example,hydrochloric acid, sulfuric acid, nitric acid, and perchloric acid) andorganic acids (such as acetic acid and trifluoroacetic acid) as well asion exchange materials (such as ion exchange resins) containing acidgroups. In general, the ionization constant of the acid should be atleast 10. Acids with an ionization constant greater than l are suitable.Highly concentrated hydrochloric acid such as 6 N to 12 N aqueoussolutions. are particularly preferred.

Thereactionsmay be carried out at room temperature or-at elevatedtemperatures. Thus, temperatures of from about 5C. to 340C. may be used.Very good yields are obtained at the boiling point of the aqueous acidsand these temperatures are particularlypreferred. Thus, an azeotropicmixture of 28.4% by weight of water and 71.6% by weight of perchloricacid boils at approximately 203 C. at 1 atmosphere pressure. Anazeotropic mixture of 79.76% by weight of Water and 20.24% by weight ofhydrochloric acid boils at .110? C. at 760 mm. Hg pressure. The mostpreferred temperature range is from 15 C. to 150 C.

The alpha-acyl-lactams used as the starting compounds of the presentinvention are preferably obtained by the Claisen ester condensationreaction of a lactam and a carboxylic acid ester:

The compounds of the present invention are not only valuable chemicalproducts in themselves but are also suitable for use as intermediateproducts for the synthesis of other valuable chemical products, forexample, the enamines and pharmaceutical products. The nicotine andanabasine derivatives are especially useful as plant protectants and asinsecticides. The amino acids (for example, proline and hygric acid) areknown to be the building blocks out of which the complex protein molecules are constructed. The methodof producing the compounds of thepresent invention makes it possible to vary the chemical and physicalproperties of the molecules by variation of the substituents on theheterocyclic rings in the compounds. Variation of the substituents onthe carbon atoms of the ring'as well as on the'nitrogen atom causesvariations in the toxicity of the nicotine and anabasine derivatives.Thus, it is possible to vary toxicity by the molecular structure itselfrather than by mere physical dilution of a highly toxic substance or asubstance of fixed toxicity. The new compounds of the present inventionare unusually good as insecticides, especially against insects whichhave built up resistance against similar insecticides.

Details of this invention are best described by the fol-= lowingexamples. It is to be understood that the examples are submitted forillustrative purposes only and are not to be construed as limiting theinvention in any respect.

EXAMPLE I This example illustrates the general reaction:

6 when the alkyl group is CH R is H, and R is (3-pyridyl). The reactionthus becomes:

1-methyl-2,3'-pyridyl-A -tetrahydr0pyridine (N -methy l-anabasine) Tengrams of alpha-nicotinoyl-N-methyl-piperidone-Z(alpha-nicotinoyl-N-methyl-fi-valerolactarn) were dissolved in 50 cc. ofconcentrated hydrochloric acid and heated with reflux until carbondioxide evolution was complete (about 4.-5 hours). The .hydrochloricacid solution was then alkalized with a caustic alkali solution with icecooling and the solution shaken with chloroform.

The. aqueous solution was- .then continuously extracted with chloroformfor 24 hours, all the chloroform extracts were dried, chloroform removedby suction and the residue (10.5 g.) distilled in vacuo. At a boilingpoint or 133l35 C. (12 mm.)..6.1 g. of'N-methyhanabasine (76% of theory)was obtained in the form of a colorless oil. The product turned darkbrown very soon, even in a closed vessel.

Lower alkyl-substituted. (1.-4 carbonatoms) pyridyl radicals such as thepicolines,.the lutidines, the collidines, and aldehydine(2-methyl-5-ethylpyridine) react similarly and are suitable R groups."

EXAMPLE H CH; H

1 -methyl-2,3 '-pyridyl-pz peridine (d, l-N -rriethyl-anabasi ne Sixgrams of N-methyl-anabasine were dissolved in cc. of glacial aceticacid, 2 g. of a 5% mixture of palladium and carbon added and the wholehydrogenated at normal pressure on a shaking apparatus. Hydrogen takenup 0.82 l. The catalyst was filtered off, the glacial acetic acidextensively distilled off in vacuo and the residue alkalized with aconcentrated aqueous sodium carbonate solution and this was followed by12 hours. of continuous extraction with chloroform. After the chloroformhad been removed-by suction, 5.9 .gof residue were obtained which weredistilled in vacuo. N-methylanabasine was obtained in the form of acolorless oil with a boiling point of 62 C. (0.4 mm. Hg). Yield:

5.7 g. (94% of theory).

1-methyl-2,4'-pyridyl-A -tetralzydropyridine Twelve grams ofalpha-isonicotinoyl-N-methyl-piperidone-2 (alpha isonicotinoyl Nmethyl-S-valerolactam) were converted in concentrated hydrochloric acidas described in Example I. CO evolution was complete after 18 hours.Distillation of 11.8 g. of the resultant crude oil product yielded, at aboiling point of 82-85 C., 8.5 g. of 1-methyl-2,4'-pyridyl-A-tetrahydropyridine (90% of theory) on the form of a colorless oil. Theproduct turned dark brown very quickly.

IR spectrum: x =1635/cm. UV absorption:

x =201 m log e=4.6. x =218 m log 6 3.92. k =236 m log 6=3.93. k =3lO mylog e=3.43. C H N -Calc.: C 75.82; H 8.10; N 16.08. Found:

C 75.88; H 8.17; N 15.74. Dipicrate: recrystallized from ethanol, yellowneedles with a melting point of 120l23 C.

N -methy l-2,2 '-pyridyl-A -tetrahydropyridine dine was obtained at aboiling point of 75 C. (0.2 mm.).

The product was a colorless oil which turned dark brown after a shorttime.

IR spectrum: x =1627/cm.

C H N (174.2)Calc.: C 75.82; H 8.10; N 16.08.

Found: C 75.26; H 8.12; N 15.65.

Monopicrate: recrystallized from ethanol; yellow-orange needles with amelting point of 127-129 C.

R4 where R R are lower alkyl groups (1-4 carbon atoms) or hydrogen.Suitable aryl groups include tolyl, cumyl, duryl, mesitylyl, xylyl, andcymyl radicals as well as the unsubstituted phenyl groups. When R -R arehydrogen atoms, the compound 1-methyl2-phenyl-A -tetrahydro pyridine isformed.

1 -methyl-2-phenyl-A -1etrahydropyridine Sixty grams of alpha-benzoyl-N-methyl-piperidone-2 were heated under reflux in 300 cc. ofconcentrated hydrochloric acid for 24 hours (until carbon dioxideevolution was complete). Hydrochloric acid solution was then worked upas described in Example I. At a boiling point of 67 C. (0.05 mm.)1-methyl-2-phenyl-A tetrahydropyridine was obtained in the form ofcolorless oil. Yield: 39 g. (81% of theory).

IR spectrum: 'y =l634/cm. IR spectrum of the hydrochloride (in CHCl UVabsorption:

X -ZOI In J. log 6:4.30. x =220 m log 6:3.89 shoulder at 276 m C H N(173.3)Calc.: C 83.19; H 8.73; N 8.09.

Found: C 83.14; H 8.83; N 7.89. Picrate: recrystallized from ethanol;bright yellow needles with a melting point of 144 C.

EXAMPLE VI R1 R: H 0 H u I 1r n R, H R3 COz I l H R2 H -0 R4 R4 H N H NI l CH3 R5 -11; 0 s I R4 wherein R -R are defined as in Example V. WhenR R are hydrogen atoms, the compound N-methyl-Z- phenyl-2-pyrroline isformed.

N-methyl-Z-phenyI-Z-pyrroline Fifteen grams ofalpha-benzoyl-N-methyl-pyrrolidone- 2, dissolved in g. of concentratedhydrochloric acid, were heated with reflux. The liberated CO was led bya weak N stream through a wash bottle of water (for removing the HCl)and into a second bottle of baryta water (barium hydroxide) for removingcarbon dioxide. After the solution had been heated for 24 hours, it wasworked up as described in Example I. Nine to ten grams of crude oil wereobtained which still gave a positive enol reaction. By fractionaldistillation in the N stream 0.5 g. of N-methyl-2-phenyl-2-pyrrolinewere obtained (5% of theory) and 9 g. of the starting acyl lactam. Afterheating for ten days, a crude oil was obtained which gave no furtherFeCl reaction. Yield 29% of theory. Bright yellow oil with a boilingpoint of 99 C. (7 mm.). UV absorption:

A ZIZ my. log =3.88. x =2S9 my log 6=3.93.

IR spectrum: 'y 1625/cm. C H N (159.2)-Calc.: C 82.97; H 8.23; N 8.80.

Found: C 83.07; H 8.15; N 9.05. Picrate: recrystallized from ethanol;yellow needles with a melting point of 139 C.

wherein R -R are as de fi ned .in 'Example 'V, and R '.R may be hydrogenor a'nfalkyl radical offror'nfl-lO carbon atoms. When.R -R and R '-R'fare -all hydrogen atoms, the compound l-phenyl-hpyrroline is formed.

Z-phenyl-I-pyrroliria A mixture of 76. g. of N ben'zoyl pyrrolidone (0.4mol) and 90 g. ofbenzoic acid 'ethyl ester (0.6 mol) 'was subjected tothe Claisen ester condensation reaction by means of potassium(pulverized potassium metal). The alphabenzoyl-N-benzoyl-pyrrolidone:2obtained after working up was dissolvedin 300. g.:of concentratedhydrochloric acid and boiled with reflux. Carbondioxide evolution (atfirst brisk) wascompleted after 3 hours. After the solution had been"alkalized with K CO and extracted with CHCl 17-18 g. of the crudereaction product were obtained which was fractionatedin vacuo.Fourteenand two-tenths grams of 2-phenyl-pyrroline were'obtained in theform of a colorlessoil'withaboiling range of 116- 118 C. (8 mm.) whichsolidified, to-white crystals. Yield of theory, based on 'N-benz oylpyrroli'done. After recrystallization from ligroin (BO-110 C.) themelting point was 44 C.

UV absorption:

A =210 my log e=4.-07. A g =244 m log e=4.33. IR spectrum: 'y =1620/crn.Picrate: recrystallized from ethanol; glossy. flakes With a meltingpoint of 198C.

EXAMPLE VIII Z-phenyl-indole Thirty-two grams of 3-benzoyl-oxindole,dissolved in 150 g. of concentrated hydrochloric acid and g. of dioxaneas solubilizing agent were boiled with reflux (and the carbon dioxideformed collected in baryta water as described in Example VI). 7 Carbondioxide evolution (at first brisk) was complete after 3 hours. Thesolution mal pressure and room temperature.

10 was alkalized with ice cooling, extracted with CHCl and the extractdried overMgSO After the solvent had been distilled off, the2-phenyl-indolewas' left in the. form of a brown crystalline mass.Yield: 15.4 g.=59%. After recrystallization from ligroin (l10 C'.),white glossy flakes were obtained having a melting point of 188 C.

UV absorption:

A =206 mg log E=4.93. X =240 m llog e=4'. 59. k =3l2 mp. log e=4.73. CI-I N (193.2)Calc.: C 87.01; H 5.74; N 7.25.

Found: C 87.12; H 5.88; N 7.33.

Twenty-seven grams of alpha-ethoxalyl-N-acetyl-pyrrolidone-2were heatedfor 1 hour with reflux in concentratedhydrochloric acid, 1 mole ofcarbon dioxide being released. The hydrochloric acid solution Wasconcentratedin vacuo to half its original volume, diluted with the samevolume ofH O, 0.5 g. of Pt0 (according to Adams) were added and theproduct hydrogenated. After .the catalyst has. been filtered ofi' andthe hydrochloric acid'solution boileddown,'d,l-proline hydrochloride wasobtained as a crude "product. Bycharging this product to anion exchangecolumn containing'Amberlite IR 45 and fwashingwith 1.5 liters of waterthe hydrochloric acid 'was removed. After the solution was concentratedby "evaporation o'fthe solvent, 9 g. (78% of theory) of d,l-

proline was obtained.

Ten grams (0.05 mol) of alpha-ethoxalyl-N-methylpyrrolidone-Z weredissolved in 60 cc. of concentrated HClandheated with reflux for 20hours. The solution was concentrated to a volume of 50 cc. and aftercooling filtered off from any alpha-oxalyl-N-methyl-pyrrolidone-2 whichmay have crystallized out. The filtrate was diluted with Water, 0.5 g.of PtO added, and hydrogenated at nor- The solution was filtered 01ffrom the catalyst and concentrated. The hygric acid hydrochloride withmelting point 187 C. (9 g.=% of theory) which crystallized out wasdesalted by charging it to a weakly basic ion exchanger. After tion ofthe solvent in vacuo.

' l l the aqueous washing liquid had been concentrated, 6.3 g. of d,l-hygric acid was obtained (85% of theory). Melting point 174-175 C.(recrystallized from ethanol/ ether).

IR spectrum: =162O/ cm.

UV spectrum: h =199 m (log 2.24).

C H O N (129.2)Calc.: C 55.79; H 8.58; N 10.85.

Found: C 55.65; H 8.25;N 11.01.

d,l-N-methyl-pipeclic acid Twenty-one and three-tenths grams (0.1 mol)of alphaethoxalyl-N-methyl-pyrrolidone-2 was suspended in 100 cc. of 6 NHCl and heated to the boiling point. The solution was held at theboiling temperature with reflux for 5 minutes and 60 cc. of thehydrochloric acid was then distilled in vacuo. The residue was dilutedwith 40 cc. of water, 0.5 g. of Pt0 was added and the product washydrogenated at normal pressure. The solution was then filtered off fromthe catalyst and concentrated by evapora- Seventeen and nine-tenthsgrams of N-rnethyl-pipecolic acid hydrochloride (100% of theory) wereleft. Recrystallized from ethanol/ether, melting point 193-194 C. Thehydrochloride was dissolved in a small amount of water and freed fromthe hydrochloric acid by charging the product to a weakly basic ionexchanger. After the aqueous solution had been concentrated in vacuo,14.3 g. (100% of theory) of N-methylpipecolic acid was obtained.Recrystallized from ethanol/ ether, melting point 205-208" C.

UV spectrum: M :199 m (log 6 2.23).

IR spectrum: 'y =1615/cm.

C H O N (143.2)Cale.: C 58.72; H 9.15; N 9.78.

Found: C 58.35; H 9.22; N 9.82.

EXAMPLE XII Zilyosmine (3 [pyrrolin-Z-yl] -pyridil1e) Sixty-six grams of1,3-dinicotinoyl-pyrrolidone (FeCl reaction: green) was dissolved inconcentrated HCl and boiled with reflux. Carbon dioxide evolution (atfirst brisk) was complete after 3 hours. The solution was cooled,alkalized with K CO and extracted with CHCl After the solution had beendried and the solvent distilled off, myosmine was obtained in the formof a yellow oil which soon crystallized and distillation (boiling point129 C. at 7 mm.) or recrystallization from ligroin (SO-110 C.) gavewhite glossy flakes having a melting point of 44 C. and a distinctiveodor. Yield: 28.5

12 g.=39% of theory (basic on nicotinic acid ethyl ester) or 86% oftheory (based on 1,3-dinicotinoyl pyrrolidone crude product).

IR spectrum: 'y =1620/cm.

C H N (146.2)Calc.: C, 73.94; H, 6.90; N, 19.16.

Found: C 73.71; H 6.66;N 18.68.

Dipicrate: (from ethanol/H O, 50/50) yellow crystals,

melting point 184 C.

EXAMPLE XIII COCgHy (I) O C3117 Gamma-coniceine(2-propyl-tetrahydr0pyridine) Twenty-five grams ofalpha-butyryl-N-butyryl-piperidone-2 (crude product) were suspended incc. of 10 N HCl and heated under reflux for 3 hours until CO evolutionwas complete. The solution was saturated with K CO and exhaustivelyextracted with chloroform. After drying over Na SO the chloroform wasdistilled off and the residue fractionated in vacuo. Nine grams (71% oftheory) of gamma-coniceine was obtained in the form of a colorless oilhaving a boiling point of 60-62 C. (11 mm.) n =1.4602. Picrate: yellowprisms from ethanol, melting point 76-78 C.

NMR-structural examination of gamma-coniceine and N-methyl-gamma-coniceine The positions of the double bond in Examples VII,XII and XIII have been confirmed by Nuclear Magnetic Resonance (NMR)spectroscopy. The NMR spectra confirm for gamma-coniceine the A-tetrahydropyridine structure and for N-methyl-gamma-coniceine the A-tetrahydropyridine structure.

Although some authors describe gamma-coniceine to be 2-propoyl-A-tetrahydropyridine (A) A B C it has been found that gamma-coniceinedoes not show a NH-absorption band in its IR spectrum. On the otherhand, the spectrum shows a strong absorption band at 1660 cm.- which maybe assigned to a CN-double bond. For this reason structure B appears tobe more likely. It was confirmed by NMR-spectroscopy.

The NMR-spectrum of I should give a signal in the region of olefinicprotons which could not be found. The signal of the alpha-protons shouldbe found near 7.31 and the NH-signal near 8.01- as they are found inpiperidine. The NMR-spectrum of gamma-coniceine yields only two signalgroups (see table) which can be assigned to structure B. To prove theassignment the product was hydrogenated and its NMR-spectrum recorded.Now three signal groups were found: The signal of the alpha-protons at7.171-, of the NH-proton at 7.95-r and of the aliphatic protons in therange from 8.6 to 9.1-r, which is in complete agreement with thespectrum of the unsubstituted piperidine.

Both observations, the fact that the NMR-spectrum of gamma-coniceineyield no signal in the region of olefinic protons and the unusually low1- value of the signal of the alpha protons can only be understood forthe structure given by formula B.

The NMR-spectrum of N-methyl-gamma-coniceine consists of four signalgroups. The assignment is given in Table I. After hydrogenation thesignal at 5.77-r (olefinic proton) disappears, so that the NMR-spectrumis in full agreement with the structure given by formula C.

TABLE I.SIGNAL POSITIONS AND ASSIGNMENTS FOR THE DISCUSSED SUBSTANCESAND SOME RELATED COMPOUNDS Signal position for Aliphatic H in OlefinicBetaand Substance H in GammaPosition Beta- Alplia- NH or Propyl SidePosition Protons N-CH1 Chain Protons 5. 77 7. 23 7. 49 8. 07-9. 12 H Ca1 1 CH2 q 7. l7 7. 95 8. 67,8. 80, 9. O9

H LN Ca 7 f [5' 7. 33 8. 05 8. 54 O. N/C! H *T-VfilllQS are defined andexplained in Applications of Nuclear Jae formulae which comprises:

(a) heating the compound of the formula wherein:

Magnetic Resonance Spectroscopy in Organic Chemistry by L. M.

man on pp. 547'8 (1959).

R is a member of the group consisting of hydrogen and a radical of up to20 carbon atoms selected from alkyl, aryl, alkaryl, carboxyl,carbalkoxy, and pyridyl, thiophenyl, furanyl and lower alkyl furanyl;

Y is a carbon atom bridge of from 2 to 3 carbon atoms substituted with amember of the group consisting of hydrogen and a radical containing upto 12 carbon atoms selected from alkyl, aryl, alkaryl, carboxyl andcarbalkoxy; and

Z is a member of the group consisting of hydrogen, alkyl of 1 to 12carbon atoms and alkanoyl of 1 to 20 carbon atoms,

(b) in liquid phase in the presence of an acid having an ionizationconstant greater than 10' at tem- H2 at EH N/\R aliryl which comprises(a) heating the compounds of the formula ii I 1 alkyl wherein alkyl isfrom 1-12 carbon atoms; wherein: R is a member of the group consistingof hydrogen and a radical of up to 20 carbon atoms selected from alkyl,aryl, alkenyl, carboXyl, carbalkoxy, and pyridyl, thiophenyl, furanyland lower alkyl furanyl; R is alkyl of 1 to 4 carbon atoms,

(b) in liquid phase in the presence of an acid having an ionizationconstant greater than 10- at temperatures of from about 5 C. to 340 C.to give the unsaturated product, and

(c) hydrogenating the resulting product to form the correspondingsaturated product.

3. The process for the preparation of N-heterocyclic amines of theformula a lkyl which comprises:

(a) heating the compound of the formula i alkyl wherein alkyl is from1-12 carbon atoms; wherein: R is a member of the group consisting ofhydrogen and a radical of up to 20 carbon atoms selected from alkyl,aryl, alkaryl, carboxyl, and pyridyl, thiophenyl, furanyl and loweralkyl furanyl;

R is alkyl of 1 to 4 carbon atoms,

(b) in liquid phase in the presence of an acid having an ionizationconstant greater than 10- at temperatures of from about 5 C. to 340 C.to give the unsaturated product, and

(c) hydrogenating the resulting product to form the correspondingsaturated product.

4. The process for the preperation of N-methyl-anabasine which comprisesheating a-nicotinyl-N-methyl-fivaler-olactam in the presence ofconcentrated hydrochloric acid.

5. The process for the preparation of 1-methy1-2,4'- pyridyl-A-tetrahydropyridine which comprises heatinga-isonicotinoyl-N-methyl-fi-valerolactam in the presence of concentratedhydrochloric acid.

6. The process for the preparation of N-methyl-2,2'- pyridyl-A-tetrahydropyridine which comprises heating 15 16a-picolinoyl-N-methyl-piperid one-2 in the presence of con- OTHERREFERENCES centrated hydrochlonc acld' Henry: The Plant Alkaloids, 4thed. pp. 35-53 (Blakiston) (1949). References Cited by the ExammerK-Iingsberg: Pyridine and Its Deriv., Part 1, pp. 90,

UNITED STATES PATENTS 5 246-7 (1960). 2,748,134 5/1956 St 11 et 1.260-294 2,854,457 9/1958 ciglak 26O 296 WALTER A. MODANCE, PrmzaryExaminer.

2,882,273 4/ 1959 Holdrege 260294 DUVAL T. MCCUTCHEN, NICHOLAS S. RIZZO,2,888,461 5/1959 Klingsberg 260296 JOHN D. RANDOLPH, Examiners.

1. THE PROCESS FOR THE PREPARATION OF N-HETROCYCLIC AMINES OF THE GROUPCONSISTING OF COMPOUNDS OF THE FORMULAE
 4. THE PROCESS OF THEPREPERATION OF N-METHYL-ANABASINE WHICH COMPRISES HEATINGA-NICOTINYL-N-METHYL-BVALEROLACTAM IN THE PRESENCE OF CONCENTRATEDHYDROCHLORIC ACID.